During pregnancy, women are at an increased risk of infectious complications, leading to potentially devastating effects on both maternal and fetal morbidity and mortality. The 2009 H1N1 influenza pandemic was a notable example, in which pregnancy was associated with an 8-fold increased risk of death among adults with H1N1, with the highest incidence of death in pregnant women occurring in the 3rd trimester. Levels of placental growth factor (PlGF) increase during normal 3rd trimester of pregnancy, correlating with this period of highest risk for infectious complications. Our hypothesis is that PlGF contributes to an exaggerated, pathologic pro-inflammatory state in response to toll-like receptor (TLR) pathway activation, directly contributing to maternal and fetal morbidity and mortality in the setting of infectious complications. Our preliminary data support our hypothesis, and we have determined that PlGF significantly enhances TLR-mediated inflammatory cytokine production by primary mononuclear phagocytes, modulating cytokine gene transcription via activation of the TLR-pathway. The objectives of this study are to define molecular mechanisms of this `PlGF/TLR' effect, and to determine the contribution of the trophoblast and fetal macrophages to this inflammatory response, with an ultimate goal of developing targeted pharmacological therapies specifically for women critically-ill with infection-mediated inflammatory complications during pregnancy. We have 3 specific aims: Aim 1 is designed to identify molecular determinants contributing to PlGF-mediated TLR-pathway hyper-reactivity in primary monocytes, Aim 2 seeks to determine mechanisms by which placental trophoblasts and macrophages enhance TLR-mediated inflammatory signaling, Aim 3 is designed to determine the effect of in vivo PlGF priming during pregnancy on TLR- activation of maternal monocytes. The training objective of this proposal is to achieve independence as a physician- scientist with expertise in 1) placental biology 2) the role of the trophoblast in driving inflammatory complications, and 3) intrinsic regulators of TLR-pathway activation. This proposed research is part of a personalized 4-year training and career development research program for the applicant. The applicant is well-suited to perform the studies proposed in this application, given her preliminary studies on the PlGF/TLR effect in circulating mononuclear phagocytes, and her multi-disciplinary and cross-institutional mentorship committee involving the fields of Hematology, Molecular Biology and Cell Signaling, Gene Profiling and Bioinformatics, Obstetrics/ Gynecology and Maternal Fetal Medicine, and Placental Biology. Her lead mentor is an extramurally funded, internationally recognized scientist with expertise in Placental Origins of Disease. Moreover, the environment at the applicant's institution is uniquely situated to ensure the successful completion of the aims of this proposal, as an internationally recognized center of expertise in placental biology and placental origins of disease, and the institution is fully committed to the applicant's long-term career development. This translational research will have a significant impact on the field of maternal-fetal medicine, by determining mechanisms involved in the increased vulnerability during pregnancy to severe infectious and inflammatory complications, pathways that can potentially be targeted in pregnant women critically ill with infection-mediated inflammatory complications.